Platelets are non-nucleated blood cells which play a main role in physiological hemostasis and pathologic thrombus generation. Platelets are constantly produced in vivo from megakaryocytes, precursor cells. Platelets are, like other blood cells, produced from multipotential stem cells. Multipotential stem cells become megakaryocytic precursor cells, from which megakaryoblasts, promegakaryoblasts and megakaryocytes are formed in this order. During maturation of the megakaryocytes, immature megakaryocytes conduct DNA synthesis only without cell division to form polyploids. Thereafter, maturation of cytoplasms begins to form platelet separation membranes, and the cytoplasms are split to release platelets.
Meanwhile, a decrease in platelets due to various hematopoietic disorders in chemotherapy, radiotherapy or the like of anemia, myelodysplastic syndrome or malignant tumor induces serious conditions such as invitation of bleeding tendency. Therefore, various attempts of technical development for increasing platelets have been made for the purpose of treating the same. At present, a potent method for treating thrombocytopenia is platelet transfusion. However, a sufficient amount of platelets is not yet supplied, and life of platelets transfused is short. For these reasons, it is hard to satisfactorily improve thrombocytopenia. Moreover, platelet transfusion involves problems such as viral infection, production of alloantibody and graft versus host disease (GVHD). Accordingly, the development of medications for relaxing an inhibitory state of a hematopoietic function induced by various diseases or therapies and accelerating recovery of the number of platelets has been expected.
Under these circumstances, it has been reported that thrombopoietin (hereinafter referred to as TPO) which is a main factor participating in division to megakaryocytic cells and is a c-Mpl ligand is cloned to stimulate division and growth of megakaryocytic cells and accelerate production of platelets (Kaushansky K. et al., Nature, 369, 568-571, 1994; Non-patent Document 1). TPO has already been subjected to a clinical test as a platelet increasing agent, and usefulness and tolerance in humans are being confirmed. However, in a clinical test of PEG-rHuMGDF (TPO whose 163rd amino acid seen from the N-terminal has been modified with polyethylene glycol) which is a type of TPO, a neutralizing antibody has been confirmed (Li J. et. al., Blood, 98, 3241-3248, 2001: Non-patent Document 2, and Basser R. L. et al., Blood, 99, 2599-2602, 2002: Non-patent Document 3). Accordingly, there is a fear of TPO immunogenicity. Further, since TPO is a protein, it is decomposed in digestive organs, and is thus not practical as an oral administration drug. For the same reason, a low-molecular peptide is not considered either to be practical as an oral administration drug. Under these circumstances, the development of an orally administrable non-peptide c-Mpl ligand with less immunogenicity has been under way for treatment of thrombocytopenia.
As the foregoing compounds, benzodiazepine derivatives (Patent Document 1), acylhydrazone derivatives (Patent Document 2), diazonaphthalene derivatives (Patent Document 3), pyrrocarbazole derivatives (Patent Document 4), pyrrophenanthridine derivatives (Patent Document 5) and pyrrophthalimide derivatives (Patent Document 6) have been known.
WO 01/07423 (Patent Document 7) describes that compounds represented by the following general formula (VII) have a platelet increasing function.
(As to symbols in the formula, refer to the document.)
The document describes the compounds containing thiazole which may be substituted as X1 and —NHCO— as Y1. In the present invention, however, R3 in the compounds of the invention is not substituted with a substituent having an A1 group such as a thiazolyl group in the document. Moreover, regarding compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom, there is not any concrete disclosure by Examples or the like in the document.
WO 01/53267 (Patent Document 8) describes that compounds represented by the following general formula (VIII) have a platelet increasing function.X1—Y1-Z1-W1  (VIII)(As to symbols in the formula, refer to the document.)
The document describes the compounds containing thiazole which may be substituted as X1 and —NHCO— as Y1. In the present invention, however, R3 in the compounds of the present invention is not substituted with a substituent having a W1 group in the document. Regarding compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom, there is not any concrete disclosure by Examples or the like in the document.
WO 02/62775 (Patent Document 9) describes that compounds represented by the following general formula (IX) have a platelet increasing function.
(As to symbols in the formula, refer to the document.)
The document describes the compounds in which the 5-position of 2-acylaminothiazole is directly substituted with a nitrogen atom. However, it does not describe compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom in the present invention.
WO 03/062233 (Patent Document 10) describes that compounds represented by the following general formula (X) have a platelet increasing function.
(As to symbols in the formula, refer to the document.)
The document describes the compounds in which the 5-position of 2-acylaminothiazole is directly substituted with a nitrogen atom. However, it does not describe compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom in the present invention.
In addition to the foregoing Patent Documents 7 to 10, 2-acylaminothiazole compounds are described as cholecystokinin and gastrin receptor antagonists in U.S. Pat. No. 3,199,451 (Patent Document 11) or as compounds having antiinflammatory characteristics in Chemical and Pharmaceutical Bulletin, 25, 9, 2292-2299, 1977 (Non-patent Document 4). However, none of them indicate at all the platelet increasing function in the present invention.
Under such circumstances, the development of an orally administrable non-peptide c-Mpl ligand with less antigenicity has been in demand for treatment of thrombocytopenia.
[Patent Document 1]JP-A-11-152276[Patent Document 2]WO 99/11262 pamphlet[Patent Document 3]WO 00/35446 pamphlet[Patent Document 4]WO 98/09967 pamphlet[Patent Document 5]JP-A-10-212289[Patent Document 6]JP-A-2000-44562[Patent Document 7]WO 01/07423 pamphlet[Patent Document 8]WO 01/53267[Patent Document 9]WO 02/62775 pamphlet[Patent Document 10]WO 03/062233 pamphlet[Patent Document 11]Patent No. 3199451[Non-Patent Document 1]Nature, 1994, No. 369, p. 568-571[Non-Patent Document 2]Blood, 2001, vol. 98, p. 3241-3248[Non-Patent Document 3]Blood, 2002, vol. 99, p. 2599-2602[Non-Patent Document 4]Chemical and Pharmaceutical Bulletin,1977, vol. 25, No. 9, p. 2292-2299
[Non-patent Document 1] Nature, 1994, No. 369, p. 568-571
[Non-patent Document 2] Blood, 2001, vol. 98, p. 3241-3248
[Non-patent Document 3] Blood, 2002, vol. 99, p. 2599-2602
[Non-patent Document 4] Chemical and Pharmaceutical Bulletin, 1977, vol. 25, No. 9, p. 2292-2299